Prophylactic Corticosteroid Use with Axicabtagene Ciloleucel (Axi-Cel) in Patients (Pts) with Relapsed/Refractory Large B-Cell Lymphoma (R/R LBCL): 2-Year Follow-up of ZUMA-1 Cohort 6

Introduction: Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for the treatment of adults with R/R LBCL after ≥2 lines of systemic therapy and for R/R LBCL within 12 months of first-line chemoimmunotherapy. In Cohorts 1+2 of the ZUMA-1 Phase 1/2 study of axi-cel in refractory LBCL, 11% and 31% of pts experienced Grade ≥3 cytokine release syndrome (CRS) or neurologic events (NEs), respectively, and the objective response rate (ORR) was 83% (58% complete response [CR] rate) with ≥2 y of follow-up (median, 27.1 mo; Locke, et al. Lancet Oncol. 2019;20:31-42). ZUMA-1 safety management Cohort 6 (N=40), which evaluated whether prophylactic and earlier corticosteroids and/or tocilizumab could improve safety outcomes, demonstrated an improved safety profile (no Grade ≥3 CRS; 15% Grade ≥3 NEs) versus Cohorts 1+2, and high, durable response rates (95% ORR, 80% CR rate, and 53% ongoing response rate) with ≥1 y of follow-up (Oluwole, et al. Blood. 2021;138:2832). Here, 2-y updated outcomes are reported.

Methods: Eligible pts with R/R LBCL underwent leukapheresis (followed by optional bridging therapy) and conditioning chemotherapy, followed by a single axi-cel infusion. Corticosteroid prophylaxis (once-daily oral dexamethasone 10 mg) was given on Days 0 (before axi-cel), 1, and 2. Compared with Cohorts 1+2, corticosteroids and/or tocilizumab were given earlier for CRS and NE management (Oluwole, et al. Br J Haematol. 2021;194:690-700). The primary endpoints were incidence and severity of CRS and NEs. Secondary endpoints included ORR (investigator-assessed), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and CAR T-cell levels in blood.

Results: As of December 16, 2021, the median follow-up time for the 40 treated pts was 26.9 mo. All pts had treatment-emergent adverse events (TEAEs), and all reported Grade ≥3 events. The most common Grade ≥3 TEAEs were neutropenia (80%), leukopenia (40%), and thrombocytopenia (28%). Since the 1-y analysis, no new CRS events were reported (no pts had Grade ≥3 CRS to date), the median time to onset of any grade CRS was 5 d, with a median duration of 4 d. The incidence of Grade ≥3 NEs increased from 15% to 18% between the 1-y and 2-y analyses. Two new NEs were observed in 2 pts: 1 pt had Grade 2 dementia (onset on Day 685 and ongoing at time of data cutoff; not related to axi-cel), and 1 had axi-cel-related leukoencephalopathy that was ultimately fatal on Day 815. The pt died in hospice care, and an autopsy was not performed. Median time to any grade NE onset was unchanged (6 d), and the median duration was similar to that in the 1-y analysis (19.0 d vs 18.5 d, respectively).

To date, 60% of pts had any grade infections, with 28% Grade ≥3; 5 pts had COVID-19 infections. Since the 1-y analysis, 6 new infections were reported. Specifically, 1 pt each had Grades 1, 2, and 5 COVID-19 infection, 1 had Grade 3 Pneumocystis jirovecii pneumonia, 1 had a Grade 3 unknown infectious episode with inflammatory syndrome, and 1 had Grade 2 herpes zoster. In total, 8 deaths occurred since the 1-y analysis: 5 due to progressive disease and 3 due to AEs (leukoencephalopathy [n=1] and COVID-19 [n=2]).

The ORR was 95% (80% CR), which was unchanged from the 1-y analysis. Median DOR and PFS were since reached (25.9 mo [95% CI, 7.8-not estimable] and 26.8 mo [95% CI, 8.7-not estimable], respectively). Median OS was still not reached. Kaplan-Meier estimates of the 2-y DOR, PFS, and OS rates were 53%, 53%, and 62%, respectively. Of 18 pts (45%) in ongoing response at data cutoff, all achieved CR as the best response. By Month 24, 14/20 pts with evaluable samples (70%) had detectable CAR T cells (vs 23/36 pts [64%] in Cohorts 1+2). Similar to the 1-y analysis, median peak CAR T-cell levels were higher in responders at 2 y (65 cells/µL [n=38]) and lower in nonresponders (18 cells/µL [n=2]).

Conclusion: With longer follow-up, the Cohort 6 toxicity management strategy continued to demonstrate the improved long-term safety profile of axi-cel in pts with R/R LBCL without compromising the response durability or survival outcomes. Further, responses remain high, durable, and similar to those observed in Cohorts 1+2 (Locke, et al. Lancet Oncol. 2019;20:31-42).

Oluwole:Pfizer: Consultancy; TG Therapeutics: Consultancy; Curio Science: Consultancy; ADC Therapeutics: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Kite, a Gilead Company: Research Funding. Forcade:Jazz: Other: Travel Support, Speakers Bureau; MSD: Other: Travel Support; Sanofi: Other: Travel Support; GSK: Speakers Bureau; Novartis: Speakers Bureau; Gilead: Other: Travel Support, Speakers Bureau. Muñoz:Fosun Kite: Consultancy; Kite, a Gilead Company: Consultancy, Speakers Bureau; Gilead/Kite: Research Funding; Genmab: Consultancy; Innovent: Consultancy; Janssen: Consultancy, Research Funding; Juno/Celgene: Consultancy; Karyopharm: Consultancy; MorphoSys/Incyte: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Pharmacyclics/AbbVie: Consultancy; Servier: Consultancy; Acrotech/Aurobindo: Speakers Bureau; AstraZeneca: Speakers Bureau; Genentech/Roche: Speakers Bureau; Seagen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Verastem: Speakers Bureau; Merck: Research Funding; Millennium: Research Funding; Portola: Research Funding; Physicians’ Education Resource: Honoraria; Incyte: Research Funding; Celgene/Bristol Myers Squibb: Speakers Bureau; Pharmacyclics/Janssen: Speakers Bureau; Celgene: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Epizyme: Consultancy; Debiopharm: Consultancy; Bristol Myers Squibb: Consultancy; Bayer: Consultancy, Research Funding, Speakers Bureau; BeiGene: Consultancy, Speakers Bureau; Alexion: Consultancy; ADC Therapeutics: Consultancy; Targeted Oncology: Honoraria; OncView: Honoraria; Kyowa Kirin: Consultancy, Honoraria, Speakers Bureau; Curio: Honoraria. de Guibert:Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Vose:Lilly: Honoraria; Janssen: Honoraria; AbbVie: Honoraria; Johnson & Johnson: Consultancy; Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy; MorphoSys: Consultancy; Kite, a Gilead Company: Research Funding; AstraZeneca: Honoraria. Bartlett:Autolus, Bristol-Meyers Squibb, Celgene, Forty Seven, Janssen, Kite Pharma, Merck, Millennium, Pharmacyclics: Research Funding; Washington University School of Medicine: Current Employment; ADC Therapeutics, Roche/Genentech, Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lin:Celgene: Consultancy, Research Funding; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Sorrento: Consultancy; Legend: Consultancy; Takeda: Research Funding; Novartis: Consultancy; Merck: Research Funding; Janssen: Consultancy, Research Funding; Gamida Cell: Consultancy; Vineti: Consultancy; Bluebird Bio: Consultancy, Research Funding. Deol:Kite, a Gilead Company: Consultancy; Janssen: Consultancy; Adicet: Consultancy. McSweeney:Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AlloVir: Research Funding; Novartis: Research Funding; Autolus: Research Funding. 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Farooq:MorphoSys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite, a Gilead Company: Honoraria; Caribou pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Checkmate Pharma: Research Funding. Minnema:Bristol Myers Squibb: Speakers Bureau; Medscape: Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Thieblemont:Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support; Novartis: Consultancy, Honoraria, Other: Travel Support, Research Funding; AbbVie: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: Travel Support; Incyte: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Other: Travel Support; Takeda: Consultancy, Honoraria, Other: Travel Support; Celgene: Consultancy, Honoraria, Other: Travel Support. Timmerman:Bristol Myers Squibb: Research Funding; Merck: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Oncovalent: Consultancy; A2: Consultancy. Stiff:Amgen: Research Funding; CRISPR Therapeutics: Consultancy; MorphoSys: Consultancy; Gamida Cell: Research Funding; Seagen: Research Funding; Bristol Myers Squibb: Research Funding; Cellectar: Research Funding; Pfizer: Research Funding; Karyopharm: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Janssen: Research Funding; Macrogenics: Research Funding; Kite, a Gilead Company: Research Funding. Avivi:Kite, a Gilead Company: Speakers Bureau; Novartis: Speakers Bureau. Tzachanis:Partner: Consultancy; EUSA: Consultancy; BMS: Consultancy, Research Funding; Takeda: Consultancy. Zheng:Gilead Sciences: Current holder of stock options in a privately-held company; Kite, a Gilead Company: Current Employment. Vardhanabhuti:Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment, Research Funding. Nater:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current holder of stock options in a privately-held company. Shen:Atara: Patents & Royalties; Kite, a Gilead Company: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Miao:Gilead Sciences: Current holder of stock options in a privately-held company; Kite, a Gilead Company: Current Employment. Kim:Kite, a Gilead Company: Current Employment; Gilead Sciences: Other: current holder of RSU in a public company. van Meerten:Kite, a Gilead Company: Consultancy, Honoraria; Janssen: Consultancy; Celgene/BMS: Research Funding; Genentech: Research Funding.